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Background

Prostate cancer is the most common malignancy in men; most are diagnosed over age 65, when age-related bone density is already decreasing and pelvic fracture is a source of morbidity and mortality. Since most men with prostate cancer survive their disease, treatment morbidity is important decisions between various modalities.

Some studies have found an increased rate of pelvic fracture associated with pelvic radiation (Oh, Red Journal 2008; Herman, Red Journal 2009), while other studies (Shahinian, NEJM 2005) suggest a lower risk of any fracture among men who receive radiation therapy (RT) for prostate cancer (PC).

The authors assessed the impact of RT modality on pelvic fracture in a population-based cohort of older men who received any form of RT for prostate cancer. They hypothesized that more conformal treatment would result in less fracture

Materials and Methods

The Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked with Medicare claims was used to identify men age 66 or older who received RT for clinically localized prostate cancer diagnosed in 1998-2005.

The primary outcome was non pathologic fracture, and was stratified by androgen deprivation therapy (ADT) use.

The impact of RT modality on pelvic fracture risk was estimated using multivariable Cox proportional hazards regression, controlling for demographic and disease characteristics, comorbidities and other treatments received.

Follow-up for fractures started at 1 year after diagnosis. All analyses were performed in the full cohort as well as and in subgroups defined by (ADT) exposure.

Results

In the SEER database, 48,337 PC patients who received RT within 12 months of diagnosis were identified

31% had 3DCRT, 18% IMRT, 8.9% EBNOS, 11% BT and 31% COMB.

Median age was 73

There were 1,054 pelvic fractures overall: 683 in men who received ADT and 371 with no ADT

At five years after diagnosis, the cumulative incidence of pelvic fracture was 2.5% (95% CI 2.2-2.7) in men who had ADT and 1.8% (95% CI 1.6-2.1) in men who had no ADT.

Controlling for patient and disease characteristics, co-morbidities and other treatments received, radiation modality had a significant impact on risk of fracture. BT was associated with almost a 30% lower risk of pelvic fracture (hazard ratio [HR] 0.72, 95% CI 0.61-0.84, p<0.001), compared with 3DCRT. IMRT and COMB were also associated with a lower risk of pelvic fracture (IMRT HR 0.86, 95% CI 0.70-1.05; COMB HR 0.82, 95% CI 0.66-1.01), but these effects were not statistically significant.

ADT exposure and type of RT were independently associated with pelvic fracture risk, but there was no interaction between these two treatments.

The brachytherapy cohort used less ADT (44%) vs. 56% for no brachytherapy, which would be expected given the lower proportion of patients with advanced disease receiving brachytherapy.

Patterns of care changed across the years: around 2005, the number of IMRT treatments exceeded 3DCRT.

Author's Conclusions

In this population-based analysis, pelvic fracture rates varied by RT modality, with lower rates observed among men who had BT.

In addition, the use of ADT adversely impacted upon the incidence of pelvic fractures in this population.

Conflicting prior evidence regarding the impact of RT on fracture risk may be explained by differences in RT modalities and the use of ADT in conjunction with radiotherapy.

Clinical Implications

More conformal treatment reduces fractures in the setting of ADT. While the radiation modality appears to be important, so is case-by-case technique. For example, even with IMRT, it is possible to deliver a high dose through femoral heads, depending on the beam orientation and constraints used. It is unclear if further dose reducing on the femoral heads could reduce fracture risk without also increasing toxicity in other organs. 3D proton technique was not specifically assessed, but fracture rates could potentially be higher than for 3D photons, if an opposed lateral field arrangement is used to deliver the entire dose. Additionally, it was not known what proportion of 3DCRT patients were treated with whole pelvis compared to prostate only fields, but it would stand to reason that whole pelvis radiation could increase the pelvic fracture rate, independent of the fact that typically patients who receive whole pelvis treatment have higher risk disease and may also be more likely to get ADT.

Other research has shown that elderly men who do not exercise lose bone density. Ito et al (Annals of Internal Medicine 2010) found that for locally advanced or high-risk localized prostate cancer treated with ADT, a bone density test followed by selective alendronate for those with osteoporosis is cost-effective.

Men should be counseled about the risk of fracture prior to starting a course of RT for prostate cancer. They should also be educated about general fracture preventive measures such as calcium and vitamin D supplementation, weight bearing exercises, and bisphosphonate therapy in the case of osteoporosis.